Dr. Bashkin received his B.A. in Chemistry from the University of California, Irvine, and his D.Phil. from Oxford, England. He was an NIH postdoctoral fellow at Harvard before joining Monsanto Corporate Research. He spent time with both Washington University and then again Monsanto (later Pharmacia and Pfizer) prior to joining UMSL in 1999 where he is now Professor of Chemistry and Biochemistry.
My group’s research has recently been directed to the interface of chemistry and biology, in areas such as "chemical genomics," the design of antiviral and anticancer agents and Green Chemistry. Much of this work involves the chemical synthesis and biochemical testing of sequence-specific DNA binding molecules designed to control gene expression. Our main goals are the invention of new chemical methods to treat and diagnose diseases and the invention of new chemical reactions to eliminate toxic waste and other undesirable features of traditional chemistry.
Recently, we have worked toward prevention of cervical cancer. Most cervical cancer is caused by certain "high-risk" forms of Human Papillomavirus (HPV), primarily HPV16 and 18. We have designed potential antiviral agents that successfully eliminate HPV16 DNA from human cells in culture, with pseudo-IC50 values as low as 27 nM. Pyrrole-imidazole polyamides are used to target viral DNA sites such as the one shown below, bound to a DNA target. We have expanded our work to HPV18; all drug discovery and development have been collaborations with Dr. Chris Fisher of NanoVir LLC. Studies of the biophysics of polyamides interacting with HPV DNA have been collaborations with Dr. Cynthia Dupureur of this department.
All of our antiviral polyamides have been rather large molecules. To study the biophysics of smaller polyamides, both to help understand the larger polyamides and to design better leads for other human diseases, we have collaborated with biophysicist W. David Wilson of Georgia State University for several years.
Earlier work was concerned with the design of ribozymes mimics: molecules capable of sequence specific cleavage of RNA by the natural transesterification/hydrolysis process. Applications include catalytic antisense agents that destroy target messenger RNA without requiring RNase H activation. We reported the first ribozymes mimic.
The chemical synthesis of the active DNA building block is shown next; ribozymes mimics are constricted by solid-phase synthesis of specific DNA sequences containing the thymidine analog that forms the active site when bound to a divalent metal ion:
In addition to this biological chemistry, I have maintained a strong interest in environmentally-benign organic chemistry, known as Green Chemistry. This work involved developing organic reactions that eliminated toxic waste associated with traditional processes.
Selected Recent Publications
″DNA binding polyamides and the importance of DNA recognition in their use as gene-specific and antiviral agents″, K. J. Koeller, G. D. Harris, K. Aston, G. He, C. H. Castaneda, M. A. Thornton, T. G. Edwards, S. Wang, R. Nanjunda, D. W. Wilson, C. Fisher and J. K. Bashkin, Med. Chem. 2014, 4, 338
“Binding studies of a large antiviral polyamide to a natural HPV sequence”’ G. He, E. Vasilieva, G. D. Harris, K. J. Koeller, J. K. Bashkin and C. M. Dupureur, Biochimie 2014, 102, 83.
”Compounds for treating papilloma virus infection”, J. K. Bashkin, K. J. Koeller, T. G. Edwards and C. Fisher, PCT Int. Appl. 2014, WO 2014065848; A2 20140501.
″Modulation of DNA-polyamide interaction by β-alanine substitutions: a study of positional effects on binding affinity, kinetics and thermodynamics″, S. Wang, K. Aston, K. J. Koeller, D. G. Harris, N. P. Rath J. K. Bashkin and W. D. Wilson, Org. & Biomol. Chem. 2014, 12, 7523
"Differential thermodynamic signatures for DNA minor groove binding with changes in salt concentration and temperature," S. Wang, A. Kumar, K. Aston, B. Nguyen, J. K. Bashkin, D. W. Boykin and D. W. Wilson, Chem. Commun. 2013, 8543.
"DNA Damage Repair Genes Controlling Human Papillomavirus (HPV) Episome Levels under Conditions of Stability and Extreme Instability," T. G. Edwards, T. J. Vidmar, K. Koeller, J. K. Bashkin and C. Fisher, PLoS One, 2013, 8, e75446
"Mapping small DNA ligand hydroxyl radical footprinting and affinity cleavage products for capillary electrophoresis," G. He, E. Vasilieva, J. K. Bashkin and C. M. Dupureur, Analytical Biochem. 2013, 439, 99.
"Human papilomavirus episome stability is reduced by aphidicolin and controlled by DNA damage response pathways," T. G. Edwards, M. J. Helmus, K. Koeller, J. K. Bashkin and C. Fisher, J. Virol. 2013, 87, 3979.
"Guanidinyl-substituted polyamides useful for treating human papilloma virus," J. Bashkin, T. G. Edwards, C. Fisher, G. D. Harris and K. J. Koeller, U.S. Pat. Appl. Publ. 2013, US 20130090362 A1 20130411.
"Correlation of Local Effects of DNA Sequence and Position of Beta-Alanine Inserts with Polyamide-DNA Complex Binding Affinities and Kinetics," S. Wang, R. Nanjunda, K. Aston, J. K. Bashkin and W. Wilson, Biochemistry, 2013, 51, 9796.
"Promoter scanning of the human COX-2 gene with 8-ring polyamides: Unexpected weakening of polyamide–DNA binding and selectivity by replacing an internal N-Me-pyrrole with β-alanine," J. K. Bashkin, K. Aston, J. P. Ramos, K. J. Koeller, R. Nanjunda, G. He, C. M. Dupureur and W. D. Wilson, Biochimie, 2013, 95, 271.
"Fluorescence assay of polyamide-DNA interactions," C. M. Dupureur, J. K. Bashkin, K. Aston, K. J. Koeller, K. R. Gaston and G. He, Analytical Biochem. 2012, 423, 178.
"HPV episome levels are potentially decreased by pyrrole-imidazole polyamides," T. G. Edwards, K. J. Koeller, U. Slomczynska, K. Fok, M. Helmus, J. K. Bashkin and C. Fisher, Antiviral Res. 2011, 91, 177.
"Compounds Designed to Bind Conserved Regions of Human Papillomavirus (HPV) DNA show Broad-spectrum Activity Against High-risk Genotypes," J. K. Bashkin, T. Edwards, K. Koeller, U. Slomczynska and C. Fisher, Antiviral Res. 2009, 82, A54.
"Effects of Anti-human Papillomavirus (HPV) Disease Agents on HPV Episome Levels In Vitro: Cidofovir, Podophyllotoxin, and Pyrrole–Imidazole Polyamides," T. G. Edwards, K. J. Koeller, J. K. Bashkin and C. Fisher, Antiviral Res. 2009, 82, A68.